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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• This invention relates to heterocyclic derivatives that are inhibitors of dopamine active transporter protein (DAT) and to pharmaceutical compositions containing, and the uses of, such derivatives.
• DAT dopamine active transporter protein
• the spirocyclic derivatives of the present invention are inhibitors of human dopamine active transporter protein (DAT) and have a number of therapeutic applications, particularly in the treatment of sexual dysfunction, affective disorders, anxiety, depression, chronic fatigue, Tourette syndrome, Angelman syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), obesity, pain, obsessive-compulsive disorder, movement disorders, CNS disorders, sleep disorders, narcolepsy, conduct disorder, substance abuse (including smoking cessation), eating disorders, and impulse control disorders.
• DAT dopamine active transporter protein
• Dopamine is a neurotransmitter which has a fundamental role in cognitive, affective, motor, motivational and reward-related functions. Following evoked action potentials DA is released into the synaptic cleft and this DA signal is extinguished by reuptake of DA into pre-synaptic neurons by DAT and by amine diffusion and local metabolism via enzymatic degradation. Dysfunction of the dopaminergic system is implicated in numerous CNS disorders and consequently DAT has been the focus of research into a number of these conditions and strong associations exist between abnormal DAT expression and/or function and disease.
• DAT DAT
• Stimulants such as amphetamine and methylphenidate have multiple pharmacological activities including effects on synaptic levels of DA, noradrenaline (NE) and serotonin (5-HT).
• NE noradrenaline
• 5-HT serotonin
• DAT inhibitors are also used to treat CNS disorders.
• Bupropion which is prescribed as an antidepressant and a smoking cessation aid has a significant DAT component to its pharmacological activity, although it carries an increased seizure risk.
• Modafinil which is prescribed as a treatment for narcolepsy, excessive daytime sleepiness and shift work sleep disorder has been shown to inhibit DAT as part of its pharmacological mechanism of action.
• SERT serotonin transporter
• NET noradrenaline transporter
• Drugs that inhibit SERT and NET have been burdened with multiple adverse side effects such as nausea (5), sexual dysfunction (6), increased suicide risk (7) for drugs that elevate 5-HT levels and elevated heart rate and blood pressure (8, 9) for drugs that increase noradrenaline levels.
• ADD and ADHD are neurodevelopmental psychiatric, behavioural and cognitive disorders characterised by concentration deficits, inner restlessness/hyperactivity, and impulsivity. These are the most common behavioural disorders amongst children, with a prevalence of 5-10% of the general population. It is widely believed that the symptoms of these disorders result from a dopaminergic and/or noradrenergic hypofunction. There is a wealth of information showing that the core symptoms of ADHD are influenced by changes in dopaminergic function (10) and hence a DAT inhibitor which would raise synaptic DA levels, should be efficacious. Current treatments for ADD/ADHD include the stimulants amphetamine and methylphenidate.
• Tourette's syndrome is a neuropsychiatric disorder characterised by motor and/or phonic tics. It normally presents during childhood and is poorly treated with drugs. Studies have postulated that one aspect underlying Tourette's is dopaminergic dysfunction whereby tonic/phasic dysfunction results in reduced synaptic DA levels and consequently higher levels in axon terminals leading to increased stimulus dependent release. Further studies have shown that post-mortem tissue from Tourette's patients showed elevated levels of DAT in the frontal lobe (14) and that polymorphisms in DAT are associated with the occurrence of Tourette's. This was further supported in a clinical study of drug na ⁇ ve children which showed and increased specific/non-specific DAT binding ratio in those with Tourette's (15). These findings suggest that a selective DAT inhibitor may provide symptomatic relief for Tourette's patients.
• OCD obsessive compulsive disorder
• ODD oppositional defiant disorder
• conduct disorder have also been associated with DAT.
• OCD patients have been shown to have an increased specific/non-specific DAT binding ratio (16) and this ratio was altered following treatment with SSRIs which are commonly used to treat OCD.
• SSRIs which are commonly used to treat OCD.
• abnormal dopamine function and/or dopamine turnover have been implicated in ODD
• conduct disorder and other related behavioural disorders (17) and polymorphisms in DAT have been implicated as a risk factor for externalising behaviour in children.
• Studies showing that children with conduct disorder display disrupted reinforcement signalling and a response to reward have also suggested that modulation of synaptic dopamine levels could be a therapeutic option for these disorders presenting the opportunity to use a selective DAT inhibitor to treat these behavioural disorders.
• Sleep disorders such as narcolepsy, cataplexy, excessive daytime sleepiness and shift work sleep disorder can interfere with an individual's normal mental and physical wellbeing.
• Several of these disorders are treated with drugs that have pharmacological activity at DAT. Modafinil is widely used to treat narcolepsy and its therapeutic potential has been related to occupancy of DAT).
• Other treatments for sleep disorders include amphetamine, methamphetamine and methylphenidate, all of which have pharmacological actions at DAT.
• Preclinical studies have shown that the wake promoting effects of several of these compounds and a selective DAT inhibitor are abolished in DAT knockout mice. Together these data support the use of a selective DAT inhibitor in the treatment of sleep disorders.
• Mood disorders such as major depressive disorder, bipolar depression, seasonal affective disorder, melancholic depression, catatonic depression, postpartum depression and dysthymia represent a major medical and social burden on society and are amongst the most common of all CNS disorders. Treatment for these disorders is currently inadequate with low levels of efficacy and poor responder rates to currently available therapies. In addition many of the drugs that are the current standard of care carry unwanted side effects.
• SPECT studies in patients suffering from major depressive disorder have shown that there is an increased binding of DAT in depressed patients and that this was reversed following successful antidepressant treatment (18,19).
• antidepressants such as Nomifensine have a significant DAT inhibitory component to their mechanism of action.
• Preclinical studies investigating the behavioural phenotype of DAT knockout mice in tests for antidepressant activity have shown that genetic removal of DAT function results in antidepressant-like behaviour. This evidence is supportive for a therapeutic benefit for DAT inhibitors in mood disorders.
• a comorbid symptom of depression and an unwanted side effect of many commonly used antidepressants is sexual dysfunction (20).
• Bupropion a commonly prescribed antidepressant with a significant DAT inhibitory component to its mechanism of action has been shown to result in fewer sexual dysfunction related side effects than other antidepressants (21).
• Bupropion has been shown to reverse the sexual dysfunction caused by SSRIs.
• Preclinical studies have shown an effect of Bupropion on sexual behaviour in rats which is supported by clinical evidence that the drug is effective in treating women suffering from hypoactive sexual desire disorder.
• Amphetamine has also been shown to increase sexual behaviour in male and female rats and has also been shown to reverse sexual impairment in female rats. This evidence for drugs that have pharmacological activity at DAT is an indicator that a selective and potent DAT inhibitor would be a suitable therapy for antidepressant induced sexual dysfunction as well as for treating sexual dysfunction in non-depressed patients.
• DAT polymorphisms have been implicated in anxiety disorders such as post traumatic stress disorder (PTSD) (22).
• PTSD post traumatic stress disorder
• Phenelzine which elevates dopamine levels in the brain amongst its actions has been shown to reduce the symptoms of PTSD.
• Bupropion which has a significant DAT inhibitory component to its mechanism of action is also prescribed for patients with anxiety disorders and has been shown to be efficacious in patients with panic disorder, further supporting the potential of DAT inhibitors in these conditions.
• Movement disorders such as Parkinson's disease (PD) and Restless Leg Syndrome (RLS) are common neurological disorders which have been treated with therapies that result in elevated brain dopamine.
• PD is characterised by a loss of dopaminergic neurones in the nigrostriatal pathway and a subsequent loss of dopamine.
• Drugs such as L-DOPA which is converted to dopamine in the brain have been shown to alleviate the motor symptoms of both PD and RLS. Given that DAT inhibitors also increase dopamine levels it is reasonable to assume that they would also provide therapeutic benefit in movement disorders which have been shown to have a dopaminergic component.
• Addiction and substance abuse are closely linked to dopamine and reward circuits in the brain. These substance dependencies include alcohol dependence, opioid dependence, cocaine dependence, cannabis dependence, amphetamine dependence (or amphetamine-like), hallucinogen dependence, inhalant dependence, polysubstance dependence, phencyclidine (or phencyclidine-like) dependence, and nicotine dependence.
• Preclinical studies using the selective DAT inhibitor GBR12909 and other benztropines have shown that these compounds can block the rewarding effects of drugs of abuse, such as cocaine.
• GBR12909 has been shown to block the neurochemical effects of cocaine (26, 27) as well as that of amphetamine.
• compounds which have been demonstrated to be DAT inhibitors are effective in smoking cessation. This provides evidence that a high affinity, selective DAT inhibitor could block the rewarding effects of drugs of abuse and be an effective medication to treat addiction.
• BED Binge Eating Disorder
• Eating disorders such as BED are known to have multiple components including impulse control, reward circuits and cognition, all of which are under the influence of dopaminergic signalling. It has been shown that BED sufferers have abnormal brain dopamine responses, which regulates motivation for food intake (28). In addition BED and obese patients show an abnormal frontostriatal dopamine signalling as compared to healthy controls (29). Preclinical models have shown that stimulation of the nucleus accumbens, which receives major dopaminergic input, attenuates binge eating behaviour in rats and that this effect is blocked by dopaminergic antagonists.
• Dopamine has a well-documented role in cognition and particularly in cognitive deficits seen in patients suffering from diseases characterised by abnormal dopaminergic signalling such as Parkinson's disease and schizophrenia (33). This coupled with the fact that cortical dopamine D1 receptor function is linked to NMDA mediated glutamate signalling implies that cognitive processes would be expected to be enhanced by DAT inhibitors.
• Chronic or persistent fatigue is a symptom which is common to several diseases and can be persisting or relapsing (34).
• Disease states that are associated with fatigue include chronic fatigue syndrome, post-viral fatigue syndrome, HIV, multiple sclerosis, amyotrophic lateral sclerosis (ALS), myasthenia gravis, sarcoidosis, cancer, chemotherapy treatment, celiac disease, irritable bowel syndrome, spondyloarthropathy, fibromyalgia, arthritis, infectious diseases, diabetes, eating disorders, Parkinson's disease, sleep disorders, stroke, mood disorders, drug and alcohol abuse.
• Clinical studies have shown that multiple drugs with DAT inhibition as part of their mechanism of action are effective in combating fatigue in chronically ill patients (35).
• Drugs such as modafinil, methylphenidate and bupropion which share DAT inhibition as a common pharmacological mechanism of action have been shown to be efficacious in fatigue associated with cancer, chemotherapy, sarcoidosis, ALS, depression, bipolar disorder, multiple sclerosis, Parkinson's disease, HIV and chronic fatigue syndrome. This evidence is supportive of likely efficacy for a selective and potent DAT inhibitor in fatigue associated with the diseases mentioned above.
• the compound showed potent functional activity at multiple sodium, calcium and potassium channels which would be an undesirable profile for a drug to treat CNS disorders.
• DAT inhibitors particularly those of the benztropine class
• DAT inhibitors have been shown to have pharmacological activity at multiple other receptors such as the serotonin receptor 5-HT2, the muscarinic receptor M1 and the histamine receptor H1 (37,38,39).
• These significant secondary pharmacological activities may introduce unwanted side effects to potentially therapeutically beneficial DAT inhibitors. This makes the selectivity profile of DAT inhibitors of particular importance.
• DAT inhibitors especially inhibitors that are selective over noradrenaline and serotonin, that will have utility to treat a wide range of disorders, in particular to treat depression, ADHD and eating disorders.
• Preferred compounds will possess a good pharmacokinetic profile and in particular will be suitable as drugs for oral delivery.
• Particularly preferred compounds will additionally display selectivity over noradrenaline and serotonin.
• the present invention relates to a series of heterocyclic derivatives that are inhibitors of DAT. Many of these compounds demonstrate good selectivity for DAT and are potentially useful in the treatment of sexual dysfunction, affective disorders, anxiety, depression, Tourette syndrome, Angelman syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), obesity, pain, obsessive-compulsive disorder, movement disorders, CNS disorders, sleep disorders, narcolepsy, conduct disorder, substance abuse (including cocaine abuse and smoking cessation), eating disorders, chronic fatigue and impulse control disorders.
• the invention further relates to pharmaceutical compositions of the inhibitors, to the use of the compositions as therapeutic agents, and to methods of treatment using these compositions.
• the invention provides a compound according to formula I,
• the invention comprises a compound of formula I, wherein when R 2 and R 3 come together with the carbon atoms to which they are attached to form heterocyclyl or heteroaryl, the sum of m and n is 2.
• the invention comprises a compound of formula I, wherein:
• the invention comprises a compound of formula I, wherein n is 1 and m is 0 or 1.
• the invention comprises a compound of formula I, wherein R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 11 and R 12 are all H.
• the invention comprises a compound of formula I, according to formula IA,
• the invention comprises a compound of formula I, wherein m is 1.
• the invention comprises a compound of formula I, wherein R 1 is OH.
• the invention comprises a compound of formula I, wherein L is O.
• the invention comprises a compound of formula I, wherein A is phenyl, pyridyl or pyrimidinyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, cycloalkyl, heterocyclyl, alkoxy, S-alkyl, S(O)alkyl, S(O) 2 alkyl, OH, F, Cl, —CN, OCF 3 , CF 3 , NR 13 COR 4 and NR 13 R 14 .
• A is phenyl, pyridyl or pyrimidinyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, cycloalkyl, heterocyclyl, alkoxy, S-alkyl, S(O)alkyl, S(O) 2 alkyl, OH, F, Cl, —CN, OCF 3 , CF 3 , NR 13 COR 4 and NR 13 R 14 .
• the invention comprises a compound of formula I, wherein A is phenyl, 2-pyridyl or 1,3-pyrimidinyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, F, Cl, —CN and CF 3 .
• the invention comprises a compound of formula I, wherein A is selected from the group consisting of:
• the invention comprises a compound of formula I, wherein B is phenyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, cycloalkyl, heterocyclyl, alkoxy, S-alkyl, S(O)alkyl, S(O) 2 alkyl, OH, F, Cl, —CN, OCF 3 , CF 3 , NR 13 COR 14 and NR 13 R 14 .
• the invention comprises a compound of formula I, wherein B is selected from the group consisting of:
• the invention comprises a compound selected from Examples 1 to 39.
• the present invention provides an N-oxide of a compound of formula I as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.
• the invention comprises a subset of the compounds of formula I, as defined by formula IB,
• the present invention also comprises the following aspects and combinations thereof.
• A is selected from phenyl, pyrazinyl, pyridyl and pyrimidinyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, cycloalkyl, alkoxy, S-alkyl, OH, F, Cl, —CN, OCF 3 , CF 3 and NR 13 R 14 .
• A is selected from phenyl, pyridyl and pyrimidinyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, cycloalkyl, alkoxy, S-alkyl, F, —CN and CF 3 .
• A is selected from phenyl, 2-pyridyl and 1,3-pyrimidinyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, cycloalkyl, alkoxy, S-alkyl, F, —CN and CF 3 .
• A is phenyl or pyrimidinyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, cycloalkyl, alkoxy, S-alkyl, F, —CN and CF 3 .
• B is phenyl or pyridyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, cycloalkyl, alkoxy, S-alkyl, OH, F, Cl, —CN, OCF 3 , CF 3 and NR 13 R 14 .
• B is phenyl, optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, F, Cl, —CN, OCF 3 , and CF 3 .
• B is selected from unsubstituted phenyl or phenyl substituted with 1 or 2 groups selected from F, —CN and CH 3 .
• B is phenyl substituted with one F substituent. In an aspect B is meta-fluoro-phenyl.
• R 1 is selected from H, alkyl, alkoxy, CH 2 OH, OH, F and Cl.
• R 1 is selected from CH 2 OH, OH, F and Cl.
• R 1 is selected from OH, F and Cl.
• R 1 is OH or F.
• R 1 is OH
• R 2 is selected from NR 7 R 8 , CR 11 R 12 ) 2 NR 7 R 8 , (CR 11 R 12 ) 2 NR 7 R 8 and (CR 11 R 12 ) 3 NR 7 R 8 wherein R 1 is alkyl or CH 2 OH when R 2 is NR 7 R 8 .
• R 2 is NR 7 R 8 or CH 2 NR 7 R 8 .
• R 2 is CH 2 NR 7 R 8 . In an aspect R 2 is CH 2 NH 2 .
• L is methylene, ethylene or O.
• L is methylene or O.
• L is O.
• R 9a-f are all H.
• R 13 is H.
• R 14 is H.
• n 0 or 1.
• n is 1 and m is 0 or 1. In an aspect n is 1 and m is 1.
• R 3 and R 4 are independently selected from H and alkyl.
• R 3 and R 4 are H.
• R 7 and R 8 are independently selected from H, alkyl, cycloalkyl, heterocyclyl, and C(O)R 10 , wherein when R 7 is C(O)R 10 , R 8 is H; or R 7 and R 8 may come together with the nitrogen atom to which they are attached to form heterocyclyl.
• q is 2.
• NR 7 R 8 is selected from:
• the invention comprises a subset of the compounds of formula I selected from:
• A-L-B is selected from:
• A is selected from:
• B is selected from:
• A-L-B is selected from:
• A-L-B is selected from the group consisting of (a), (b), (c), (d), (e), (f), (g), (j), (k), (m), (n), (s), (x), (y), (dd), (ee), (ll), (nn), (pp), (ss), (bbb), (ggg), (hhh) and (jjj).
• A-L-B is selected from the group consisting of (a), (b), (c), (k), (n) and (dd).
• the invention comprises a compound of formula I selected from:
• the invention comprises a compound of formula I selected from:
• the compounds of the present invention are potent inhibitors of dopamine transporters. They are therefore useful in the treatment of disease conditions for which over-activity of a dopamine transporter is a causative factor.
• the compounds of the present invention are preferably selective for dopamine transporters over noradrenaline and serotonin transporters.
• the word “selective” means the compound has an IC50 value that is at least 10-fold selective for the dopamine transporter than for each of the noradrenaline and serotonin transporters, preferably at least 20-fold, more preferably at least 30-fold, even more preferably 50-fold, most preferably 100-fold higher for the dopamine transporter than for each of the noradrenaline and serotonin transporters.
• the present invention provides a compound of formula I for use in therapy.
• the present invention also provides for the use of a compound of formula I in the manufacture of a medicament for the treatment or prevention of a condition, disease or disorder ameliorated by inhibition of a dopamine transporter.
• the present invention also provides a compound of formula I for use in the treatment or prevention of a condition, disease or disorder ameliorated by inhibition of a dopamine transporter.
• the present invention also provides a method of treatment of a condition, disease or disorder ameliorated by inhibition of a dopamine transporter comprising administration to a subject in need thereof a therapeutically effective amount of a compound of formula I.
• the condition, disease or disorder ameliorated by inhibition of a dopamine transporter includes sexual dysfunction, affective disorders, anxiety, depression, Tourette syndrome, Angelman syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), obesity, pain, obsessive-compulsive disorder, movement disorders, CNS disorders, sleep disorders, narcolepsy, conduct disorder, substance abuse (including smoking cessation), eating disorders, chronic fatigue and impulse control disorders.
• condition, disease or disorder is selected from ADD, ADHD and binge eating disorder.
• references herein to “treatment” include references to curative, palliative and prophylactic treatment.
• terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
• the compounds of the present invention and said combination agents may exist in the same or different pharmaceutical compositions, and may be administered separately, sequentially or simultaneously.
• the compounds of the invention may be administered as a combination with at least one other active pharmaceutical ingredient for the treatment of mood disorders, disorders such as depression, refractory depression, bipolar depression, and psychotic depression.
• a pharmaceutical combination may be in the form of a unit dosage form or it may be in the form of a package comprising the at least two active components separately.
• the invention relates to such pharmaceutical combinations.
• the invention therefore relates to a pharmaceutical combination comprising a therapeutically effective amount of an compound of the invention and a second active substance, for simultaneous or sequential administration.
• the invention relates to a compound of the invention in combination with another therapeutic agent wherein the other therapeutic agent is selected from:
• DAT inhibitors may be used adjunctively to treat medication induced sedation, common in diseases such as bipolar depression as well as sexual dysfunction which is a common side effect of antidepressant treatment, particularly SSRIs.
• the compounds of the invention may be administered as a combination with at least one other active pharmaceutical ingredient for the treatment of smoking cessation and mitigation of nicotine withdrawal and weight gain.
• a pharmaceutical combination may be in the form of a unit dosage form or it may be in the form of a package comprising the at least two active components separately.
• the invention relates to such pharmaceutical combinations.
• the invention therefore relates to a pharmaceutical combination comprising a therapeutically effective amount of an compound of the invention and a second active substance, for simultaneous or sequential administration.
• the invention relates to a compound of the invention in combination with another therapeutic agent wherein the other therapeutic agent is selected from:
• Nicotine replacement therapies (nicotine patches, nicotine gum, nicotine sprays, nicotine sublingual tablets, nicotine lozenges and nicotine inhalers), nicotinic full/partial agonists (Nicotine, Varenicline, Lobeline), opioid antagonists/inverse agonists (Naloxone, Naltrexone, Buprenorphine).
• the compounds of the invention may be administered as a combination with at least one other active pharmaceutical ingredient for the treatment of ADHD.
• a pharmaceutical combination may be in the form of a unit dosage form or it may be in the form of a package comprising the at least two active components separately.
• the invention relates to such pharmaceutical combinations.
• the invention therefore relates to a pharmaceutical combination comprising a therapeutically effective amount of an compound of the invention and a second active substance, for simultaneous or sequential administration.
• the invention relates to a compound of the invention in combination with another therapeutic agent wherein the other therapeutic agent is selected from:
• Norepinephrine reuptake inhibitors (Atomoxetine, Reboxetine, Viloxazine), alpha-adrenoceptor agonists (Guanfacine, Clonidine).
• the compounds of the invention may be administered as a combination with at least one other active pharmaceutical ingredient for the treatment of movement disorders such as Parkinson's disease and Restless Leg Syndrome.
• a pharmaceutical combination may be in the form of a unit dosage form or it may be in the form of a package comprising the at least two active components separately.
• the invention relates to such pharmaceutical combinations.
• the invention therefore relates to a pharmaceutical combination comprising a therapeutically effective amount of an compound of the invention and a second active substance, for simultaneous or sequential administration.
• the invention relates to a compound of the invention in combination with another therapeutic agent wherein the other therapeutic agent is selected from:
• a dopamine precursor (L-dopa) a dopaminergic agent (Levodopa-carbidopa, Levodopa-benzerazide), a dopaminergic and anti-cholinergic agent (amantadine), an anti-cholinergic agent (trihexyphenidyl, benztropine, ethoproprazine, or procyclidine), a dopamine agonist (apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, or ropinirole), a MAO-B (monoamine oxidase B) inhibitor (selegiline, rasageline or deprenyl0, a COMT (catechol O-methyltransferase) inhibitor (tolcapone or entacapone.
• a dopaminergic agent (Levodopa-carbidopa, Levodopa-benzerazide)
• Alkyl is as defined above and includes saturated hydrocarbon residues including:
• Cycloalkyl is as defined above and includes monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms, or from 3 to 6 carbon atoms, or from 3 to 5 carbon atoms, or from 3 to 4 carbon atoms. Examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is optionally substituted as stated above.
• Alkylene is a bivalent C 1-3 straight-chained alkyl radical, such as —(CH 2 )—, —(CH 2 ) 2 —, —(CH 2 ) 3 — or a bivalent C 3-4 branched alkyl radical such as —CH(CH 3 )CH, CH 2 CH(CH 3 )—, —CH(CH 3 )CH(CH 3 )—. Alkylene is optionally substituted as stated above.
• Alkoxy is as defined above and includes O-linked hydrocarbon residues including:
• Heteroaryl is as defined above. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl (optionally substituted as stated above).
• heteroaryl is selected from pyridyl, pyrazinyl, pyrimidinyl and 1,2,4-triazinyl optionally substituted as stated above.
• pyrimidinyl refers to 1,3-pyrimidinyl. Unless otherwise stated (e.g. by a chemical formula) when A is pyrimidinyl it is attached to the heterocyclic backbone at the 2-position. Unless other stated when B is pyrimidinyl it is attached to L at the 2-position.
• Heterocyclyl is defined above. Examples of suitable heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, imidazolyl, morpholine, thiomorpholine pyrazolidinyl, piperidinyl and piperazinyl (optionally substituted as stated above).
• O-linked such as in “O-linked hydrocarbon residue”, means that the hydrocarbon residue is joined to the remainder of the molecule via an oxygen atom.
• “Pharmaceutically acceptable salt” means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts.
• pharmaceutically acceptable base addition salts that can be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g.
• a compound of the invention contains a basic group, such as an amino group
• pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like.
• Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
• Prodrug refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming pro-drugs are described in ‘The Practice of Medicinal Chemistry, 2 nd Ed. pp 561-585 (2003) and in F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.
• the compounds of the invention can exist in both unsolvated and solvated forms.
• solvate is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
• solvent molecules for example, ethanol.
• hydrate is employed when the solvent is water.
• Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric, conformational and tautomeric forms, including but not limited to cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto- and enol-forms, and conformers. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis).
• An example of a compound of the invention that exhibits optical isomerism is 3-[(cyclopropylamino)methyl]-1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3-ol.
• the present invention therefore encompasses the enantiomeric forms of this compound, as illustrated below.
• the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
• the diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
• the compounds of formula I should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
• excipient is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-functional (i.e., processing aid or diluent) characteristic to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
• compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient.
• the compounds of the invention may also be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ.
• Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous.
• Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
• Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but not restricted to glucose, manitol, sorbitol, etc.), salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
• excipients such as sugars (including but not restricted to glucose, manitol, sorbitol, etc.), salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
• Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous tissue, muscular tissue or directly into specific organs.
• degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides.
• parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
• solubility of compounds of formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of co-solvents and/or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.
• the compounds of the invention may be administered orally.
• Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
• Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
• Formulations suitable for oral administration may also be designed to deliver the compounds of the invention in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said compounds.
• Means to deliver compounds in a rate-sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.
• rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion.
• rate-sustaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
• Liquid (including multiple phases and dispersed systems) formulations include emulsions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
• the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.
• the total daily dose of the compounds of the invention is typically in the range 0.01 mg and 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg depending, of course, on the mode of administration.
• the total dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
• the compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the specific examples provided herein below. Moreover, by utilising the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds that fall within the scope of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
• the compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.
• reactive functional groups e.g. hydroxy, amino, thio or carboxy
• Conventional protecting groups for example those described by T. W. Greene and P. G. M. Wuts in “Protective groups in organic chemistry” John Wiley and Sons, 4 th Edition, 2006, may be used.
• a common amino protecting group suitable for use herein is tert-butoxy carbonyl (Boc), which is readily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane.
• the amino protecting group may be a benzyloxycarbonyl (Z) group which can be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere or 9-fluorenylmethyloxycarbonyl (Fmoc) group which can be removed by solutions of secondary organic amines such as diethylamine or piperidine in an organic solvent.
• Carboxyl groups are typically protected as esters such as methyl, ethyl, benzyl or tert-butyl which can all be removed by hydrolysis in the presence of bases such as lithium or sodium hydroxide.
• Benzyl protecting groups can also be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere whilst tert-butyl groups can also be removed by trifluoroacetic acid. Alternatively a trichloroethyl ester protecting group is removed with zinc in acetic acid.
• a common hydroxy protecting group suitable for use herein is a methyl ether, deprotection conditions comprise refluxing in 48% aqueous HBr for 1-24 hours, or by stirring with borane tribromide in dichloromethane for 1-24 hours. Alternatively where a hydroxy group is protected as a benzyl ether, deprotection conditions comprise hydrogenation with a palladium catalyst under a hydrogen atmosphere.
• the compounds according to general formula I can be prepared using conventional synthetic methods for example, but not limited to, the routes outlined in the schemes below.
• Compound of formula II may be obtained by Corey-Chaykovsky epoxidation of compound I (commercially available from Sigma-Aldrich) using trimethylsulfoxonium iodide and a inorganic base, e. g. NaH, carrying out the reaction in a suitable solvent, such as DMSO, at room temperature. The reaction takes about 1 to about 2 hours to complete.
• a suitable solvent such as DMSO
• Compound of formula III may be obtained by epoxide opening of compound II using primary amines, such as methylamine, carrying out the reaction in a mixture of MeOH/water, at room temperature. The reaction takes from about 1 to about 16 hours to complete.
• primary amines such as methylamine
• Compound of formula IV may be obtained by N-protection of compound III under standard literature conditions such as by reaction with Di-tert-butyl dicarbonate, with or without the presence of a suitable base such as triethylamine, carrying out the reaction in a suitable solvent, e.g. DCM, typically at room temperature. The reaction takes about 1 to about 16 hours to complete.
• a suitable solvent e.g. DCM
• Compound of formula V may be obtained from compound IV by removing the benzyl group by hydrogenolysis, e. g. using ammonium formate and palladium on carbon, in a suitable solvent such as methanol under reflux. The reaction takes about 1 hour.
• Compound VI can be obtained from compound V by SnAr substitution with the appropriate aryl halide in a suitable aprotic solvent, e. g. DMSO, in presence of an inorganic base, such as K2CO3.
• a suitable aprotic solvent e. g. DMSO
• an inorganic base such as K2CO3.
• the reaction proceeds in a temperature range of about 25 to about 100° C. and takes about 1 to about 12 hours.
• the compound VI can be obtained from Buchwald reaction with the appropriate aryl halide in the presence of suitable transition metal catalyst, e. g. Pd 2 (dba) 3 , a suitable ligand such as DavePhos, a suitable base, such as K 3 PO 4 and like, in a suitable solvent, e. g. DME.
• the reaction is carrying out at a temperature from about 100° C. to about 110° C. and takes about 12 hours.
• Compound VII can be obtained from compound VI by removing the Boc group under acidic conditions, e. g. TFA in dichloromethane solution, typically at room temperature. The reaction takes about 1 hour.
• Compound VIII can be obtained from compound VII by coupling with the appropriate carboxylic acid (such as isobutyric acid) in the presence of coupling agents such EDC HCl and HOBt and an organic base, e. g. TEA.
• the reaction is carrying out in a suitable solvent such as dichloromethane, typically at room temperature. The reaction takes from about 3 hours to about 12 hours.
• Compound IX can be obtained treating compound VI with a fluorinated agent, such as Deoxofluor®, in a suitable solvent, such as dichloromethane, typically at 0° C. The reaction takes about 1 hour.
• a fluorinated agent such as Deoxofluor®
• a suitable solvent such as dichloromethane
• Compound IX can be obtained from compound X by removing the Boc group under acidic conditions, e. g. TFA in dichloromethane solution, typically at room temperature. The reaction takes about 1 hour.
• Compound of formula XI may be obtained by epoxide opening of compound II using secondary amines, such as pyrrolidine, carrying out the reaction in a mixture of MeOH/water, at room temperature. The reaction takes from about 2 to about 16 hours to complete.
• secondary amines such as pyrrolidine
• Compound of formula XII may be obtained from compound X by removing the benzyl group by hydrogenolysis, e. g. using ammonium formate and palladium on carbon, in a suitable solvent such as methanol under reflux. The reaction takes about 1 hour.
• Compound XIII can be obtained from compound XII by SnAr substitution with the appropriate aryl halide in a suitable aprotic solvent, e. g. DMSO, in presence of an inorganic base, such as K 2 CO 3 .
• a suitable aprotic solvent e. g. DMSO
• an inorganic base such as K 2 CO 3 .
• the reaction proceeds in a temperature range of about 45° C. to about 100° C. and takes about 1 to about 12 hours.
• Compound of formula II may be obtained by reduction of compound I (commercially available from Activate Scientific) using a suitable reducing agent, e. g. LiAlH 4 , carrying out the reaction in a suitable solvent, such as THF under reflux. The reaction takes about 2 hours to complete.
• a suitable reducing agent e. g. LiAlH 4
• Compound of formula III may be obtained by N-protection of compound II under standard literature conditions such as by reaction with Di-tert-butyl dicarbonate, with the presence of a suitable base such as triethylamine, carrying out the reaction in a suitable solvent, e.g. DCM, typically at room temperature. The reaction takes about 2 hours to complete.
• a suitable solvent e.g. DCM
• Compound of formula IV may be obtained from compound III by removing the benzyl group by hydrogenolysis, e. g. using ammonium formate and palladium on carbon, in a suitable solvent such as methanol under reflux. The reaction takes about 1 hour.
• Compound V can be obtained from compound IV by SnAr substitution with the appropriate aryl halide in a suitable aprotic solvent, e. g. DMSO, in presence of an inorganic base, such as K 2 CO 3 .
• a suitable aprotic solvent e. g. DMSO
• an inorganic base such as K 2 CO 3 .
• the reaction proceeds in a temperature of about 60° C. and takes about 1 hour.
• Compound VI can be obtained from compound V by removing the Boc group under acidic conditions, e. g. TFA in dichloromethane solution, typically at room temperature. The reaction takes about 1 hour.
• Compound of formula II can be obtained by reduction of compound I, (3-bromophenyl)(phenyl)methanone, (commercially available from Sigma-Aldrich) with a suitable reducing system, such as NaBH 4 in presence of TFA, carrying out the reaction in a suitable solvent, e. g. dichloromethane, typically at room temperature. The reaction takes about 12 hours to complete.
• a suitable reducing system such as NaBH 4 in presence of TFA
• Compound V can be obtained by Ullmann condensation between compounds III, the desired di-halogen benzene, such as 1,2-dibromo-4,5-difluorobenzene, and compound IV, the appropriate phenol, such as 3-fluorophenol, (both commercially available from Alfa-Aesar and Sigma-Aldrich respectively) in presence of a suitable catalyst, such as Cu, and a suitable base, e. g. KOH, typically at high temperature, from about 100 to about 150° C. The reaction takes about 14 hours to complete.
• compound V may be obtained by SnAr reaction between compounds III and IV in presence of an inorganic base, such as K 2 CO 3 , a suitable solvent, e. g. DMSO, at a temperature between 25° C. and about 160° C., the reaction takes from about 20 to around 12 hours to complete.
• Compound of formula VIII may be obtained via Chan-Lam coupling between compound VI, the desired boronic acid, such as phenyl boronic acid, and compound VII, the appropriate phenol, e. g. 3-bromo-2-fluorophenol (both commercially available from Sigma-Aldrich and Zentek respectively), in presence of a suitable catalyst, such as Cu(OAc) 2 , a suitable base, e. g. triethylamine, typically at room temperature. The reaction takes about 16 hours to complete.
• a suitable catalyst such as Cu(OAc) 2
• a suitable base e. g. triethylamine
• Compound XI can be obtained by reaction between compound IX, the desired boronic acid, e. g. phenyl boronic acid, and compound X, the appropriate benzene iodide, such as iodobenzene, (both commercially available from Sigma-Aldrich), in presence of a suitable oxidant, such as m-CPBA, and BF 3 Et 2 O, carrying out the reaction in a suitable solvent, such as dichloromethane.
• a suitable oxidant such as m-CPBA, and BF 3 Et 2 O
• the reaction proceeds at a temperature between 0° C. and room temperature and takes about 45 minutes to complete.
• Compound VIII may be obtained from compound XI by reaction with compound XII, a suitable phenol such as 3-fluorophenol, in presence of a suitable base, such as tBuOK, in a suitable solvent, usually THF, at a temperature between 0° C. and 40° C. The reaction takes about 1 hour.
• a suitable phenol such as 3-fluorophenol
• a suitable base such as tBuOK
• THF a suitable solvent
• Compound XIV can be obtained by chlorination of the commercially available (from Sigma-Aldrich) compound XIII, 6-(Trifluoromethyl)uracil, by treatment with a suitable chlorinating agent, such as SOCl 2 in a suitable solvent, e. g. DMF, carrying out the reaction usually at 80° C. for about 4 hours.
• a suitable chlorinating agent such as SOCl 2 in a suitable solvent, e. g. DMF
• Compound of formula XVI can be obtained by chlorination of compound XV, 2-chloro-4-(methylthio)pyrimidine (commercially available from Sigma-Aldrich), with N-chlorosuccinimide in presence of 2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithium chloride complex solution in THF/Toluene, in a suitable solvent, such as THF, typically at room temperature. The reaction takes 4 hours to complete.
• Compounds of structure XVIII and XIX can be obtained via SnAr reaction between compound XVII, e. g. 2,4-dichloro-6-methylpyrimidine (commercially available from Sigma-Aldrich), or ad hoc prepared, and a suitable partner, such as 3-fluorophenol (commercially available from Sigma-Aldrich), the reaction typically proceeds in aprotic solvent, such as DMSO, in presence of a suitable base, such as K 2 CO 3 , at a temperature between 25° C. and 110° C. The reaction takes from about 20 min to about 12 hours to complete.
• aprotic solvent such as DMSO
• a suitable base such as K 2 CO 3
• Compounds of structure XXI and XXII can be obtained via SnAr reaction between compound XX, e. g. 2,6-dichloropyridine (commercially available from Sigma-Aldrich), and a suitable phenol, such as 3-fluorophenol (commercially available from Sigma-Aldrich).
• XX e. g. 2,6-dichloropyridine
• a suitable phenol such as 3-fluorophenol
• the reaction typically proceeds in aprotic solvent, such as DMSO, in presence of a suitable base, such as K 2 CO 3 , at a temperature between 25° C. and 103° C.
• a suitable base such as K 2 CO 3
• Compound of structure XXIV can be obtained via SnAr reaction between compound XXIII, commercially available from Sigma-Aldrich, and a suitable phenol, such as 3-fluorophenol (commercially available from Sigma-Aldrich), the reaction typically proceeds in aprotic solvent, such as DMF, in presence of a suitable base, such as tBuOK, at a temperature of about 90° C. The reaction takes about 2 hours to complete.
• aprotic solvent such as DMF
• a suitable base such as tBuOK
• Compound XXVII may be obtained by reaction between compound XXV, 2,4,6-trichloropyrimidine (commercially available from Sigma-Aldrich), and a Grignard reagent XXVI, such as benzylmagnesiumchloride, (both commercially available from Sigma-Aldrich). The reaction proceeds at a temperature between ⁇ 78° C. and 20° C., and takes about 3 hours to complete.
• Compound XXVIII can be obtained by treatment of compound XXVII with MeONa, freshly obtained in situ by adding NaH in MeOH. The reaction is carried out in MeOH, typically at room temperature and takes about 1 hour to complete.
• Compound of structure XXX can be obtained via SnAr reaction between compound XXIX, commercially available from Sigma-Aldrich, and a suitable phenol, such as 3-fluorophenol (commercially available from Sigma-Aldrich), the reaction typically proceeds in aprotic solvent, such as DMF, in presence of a suitable base, such as cesium carbonate, at a temperature of around 80° C. The reaction takes about 48 hours to complete.
• aprotic solvent such as DMF
• a suitable base such as cesium carbonate
• NMR spectra may be typically recorded either on Varian instruments at 400 or 500 MHz, or on a Bruker instrument at 400 MHz.
• Chemical shifts are expressed in parts of million (ppm, ⁇ units). Chemical shifts are reported in ppm downfield ( ⁇ ) from Me 4 Si, used as internal standard, and are typically assigned as singlets (s), broad singlets (br.s.), doublets (d), doublets of doublets (dd), doublets of doublets of doublets (ddd), doublets of triplets (dt), triplets (t), triplets of doublets (td), quartets (q), or multiplets (m).
• LCMS may be recorded under the following conditions:
• DAD chromatographic traces, mass chromatograms and mass spectra may be taken on UPLC/PDA/MS AcquityTM system coupled with Micromass ZQTM or Waters SQD single quadrupole mass spectrometer operated in positive and/or negative ES ionisation mode.
• the QC methods used were two, one operated under low pH conditions and another one operated under high pH conditions. Details of the method operated under low pH conditions were: column, Acquity BEH C 18 , 1.7 ⁇ m, 2.1 ⁇ 50 mm or Acquity CSH C 18 , 1.7 ⁇ m, 2.1 ⁇ 50 mm, the temperature column was 40° C.; mobile phase solvent A was milliQ water+0.1% HCOOH, mobile phase solvent B MeCN+0.1% HCOOH.
• the flow rate was 1 ml/min.
• MDAP Semipreparative mass directed autopurifications
• the stationary phases used were, XTerra C18, XBridge C18, Sunfire C18, XSelect C18, Gemini AXIA C18.
• the length of the columns was 5, 10 or 15 cm, while the internal diameter was 19, 21 or 30 mm.
• the particle size of the stationary phases was 5 or 10 ⁇ m.
• the purifications were carried out using low pH or high pH chromatographic conditions.
• the mobile phase solvent composition was the same used for QC analysis.
• the combinations stationary/mobile phases used were: XTerra, XBridge, Sunfire, XSelect—low pH mobile phases and XTerra, XBridge, Gemini AXIA—high pH mobile phases. All the purifications were carried out with the column kept at room T.
• the flow rate used was 17 or 20 ml/min for columns of internal diameter 19 or 21 mm and 40 or 43 ml/min for columns of internal diameter 30 mm.
• the trigger for the collection of the target species was the presence of the target m/z ratio value in the TIC MS signal.
• the gradient timetable was customised on the Rt behaviour of the target species.
• RT refers to room temperature
• DMSO dimethyl sulfoxide
• DMF N,N′-dimethylformamide
• DCM diichloromethane
• EtOH ethanol
• DCE diichloroethane
• DME 1,2-Dimethoxyethane
• TEA triethylamine
• DIPEA N,N-Diisopropylethylamine
• Boc 2 O Di-tert-butyl dicarbonate
• TFA trifluoroacetic acid
• Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0)
• EDC HCl N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
• HOBt 1-Hydroxybenzotriazole hydrate
• SCX Cartridge Strong Cation Exchange Cartridge.
• 3-chloroperbenzoic acid (640 mg, 3 mmol) was dissolved in DCM (10 mL). To the solution was added 3-fluoro-iodobenzene (0.317 mL, 2.7 mmol) followed by slow addition of BF 3 OEt 2 (0.850 mL, 6.8 mmol) at RT. The resulting yellow solution was stirred at RT for 30 min, then cooled at 0° C. and 3-fluoro-phenylboronic acid (420 mg, 3 mmol) was added in one portion.
• Step b
• Step b
• Step b
• Step b
• the ability of the compounds of formula I to inhibit dopamine transporters may be determined using the following biological assays:
• affinities of the compounds of the invention for the human dopamine transporter (DAT), human norepinephrine transporter (NET) and for the human serotonin transporter (SERT) may be determined by the assays described below. Affinity is expressed in terms of inhibition constant (Ki) of the compounds of the invention for DAT, NET and SERT, and it is typically calculated from the IC 50 values obtained in competition experiments using Cheng and Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973). In the context of the present invention pKi values (corresponding to the antilogarithm of Ki) are used instead of Ki; pKi are only estimated to be accurate to about 0.3 log unit.
• CHO cells stably expressing either human DAT (hDAT-CHO) or human NET (hNET-CHO) or human SERT (hSERT-CHO) are used for the membrane preparations for radioligand binding assays using Scintillation proximity Assay (SPA) technique.
• SPA Scintillation proximity Assay
• Each cell line is cultured independently in F-12K Nutrient Mixture containing 10% of Fetal Bovine Serum (FBS) supplemented with 450 ⁇ g/ml G-418. When cells are at 70-80% of confluence 3 mM Na Butyrate was added to the cell culture medium. After 24 h of incubation, the culture medium was removed and the cells detached with Versene (DAT) or by scraping (NET and SERT).
• DAT human DAT
• NET human NET
• NET human SERT
• the affinity of the compounds of the invention to the human DAT or NET or SERT transporters is assessed by using the [ 3 H]WIN-35,428 or [ 3 H]nisoxetine or [ 3 H]citalopram binding assays in recombinant human DAT, NET and SERT membranes with the SPA technology.
• the final assay volume is 50 ⁇ L in 384 well plates.
• test compound 0.5 ⁇ L of test compound in neat DMSO or 0.5 ⁇ L of DMSO for total binding (TB) or 0.5 ⁇ L of indatraline 1 mM (10 ⁇ M final concentration) for non specific binding (NSB) are added to the assay plate.
• 50 ⁇ L of the SPA mixture is added to each well, containing: 30 ⁇ g/mL or 10 ⁇ g/mL or 25 ⁇ g/mL DAT, NET, SERT membranes, respectively; 5 nM [ 3 H]WIN-35,428 or 5 nM [ 3 H]nisoxetine or 1 nM [ 3 H]citalopram, for DAT, NET, SERT assay, respectively; 2.5 mg/mL or 1 mg/mL or 4 mg/mL WGA-PVT SPA beads (PerkinElmer RPNQ0001, for DAT, NET, SERT assay, respectively.
• the potency of the compounds of the invention in blocking the DAT function is measured using an uptake assay in a recombinant CHO cell line expressing human DAT (hDAT-CHO). Potency is measured in terms of pIC 50 by testing the compounds of invention for the inhibition of [ 3 H]-dopamine uptake in DAT-CHO cells using a SPA technology in 384 well format.
• hDAT-CHO cells are detached using Versene and added (75,000 cells/mL) to the SPA Mixture, which contains the following components in Assay Buffer (20 mM HEPES, 145 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 and 1 g/L glucose, pH 7.3): 0.02% w/v of Pluronic F127, 2 mg/mL SPA Imaging beads (RPNQ0260, PerkinElmer), 10 ⁇ M pargyline and 80 nM of [ 3 H]-dopamine.
• Assay Buffer 20 mM HEPES, 145 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 and 1 g/L glucose, pH 7.3
• the SPA Mixture is added 50 ⁇ l/well to 384 well plates containing 0.5 ⁇ L/well of test compound in neat DMSO or 0.5 ⁇ L of DMSO (control uptake) or 0.5 ⁇ L of the standard inhibitor indatraline (at 10 ⁇ M final in the assay). Plates are sealed with a Top-seal A and read using Viewlux instrument (Perkin-Elmer) at 15-30 min time intervals. The first highest signal is used for data analysis.
• the potency of the compounds of the invention in inhibiting human ERG potassium channel (hERG) tail current is assessed in a recombinant HEK293 cell line stably transfected with hERG cDNA using Rapid ICETM (Rapid Ion Channel Electrophysiology) assay.
• Rapid ICETM is an automated patch-clamp assay utilizing the PatchXpress 7000A system (Molecular Devices Corporation) or the QPatch HTX system (Sophion Bioscience A/S).
• cells are cultivated for 24 to 72 hours before recordings in minimum essential medium supplemented with 10% FBS, 1% non-essential amino acids, 1% sodium pyruvate, 2 mM L-glutamine.
• the day of the experiment cells are detached with TrypLE and prepared to be loaded on the instrument.
• For PatchXpress cells are finally resuspended in 150 ⁇ l of Extracellular Buffer whereas for QPatch cells are resuspended in 7 ml Serum-Free Media containing 25 mM Hepes and Soybean trypsin inhibitor and immediately placed in the cell storage tank of the machine.
• the composition of the Extracellular Buffer is (mM): NaCl 137; KCl 4; CaCl2 1.8; MgCl2 1.0; D-glucose 10; N 2 hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) 10; pH 7.4 with 1 M NaOH.
• the composition of the pipette solution is (mM): KCl 130; MgCl2 1.0; Ethylene glycol-bis( ⁇ -aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) 5; MgATP 5; HEPES 10; pH 7.2 with 1 M KOH.
• the voltage protocol includes the following steps: step from ⁇ 80 mV to ⁇ 50 mV for 200 ms, +20 mV for 4.8 s, step to ⁇ 50 mV for 5 s then step to the holding potential of ⁇ 80 mV.
• Compounds of the invention are dissolved in DMSO and diluted in Extracellular Buffer to achieve final test concentrations (0.1, 1 and 10 ⁇ M) in 0.1% DMSO.
• the voltage protocol is run and recorded continuously during the experiment.
• the vehicle, corresponding to 0.1% DMSO in Extracellular Buffer, is then applied for 3 min followed by the test substance in triplicate.
• the standard combined exposure time is 5 min.
• the average of tail current amplitude values recorded from 4 sequential voltage pulses is used to calculate for each cell the effect of the test substance by calculating the residual current (% control) compared with vehicle pre-treatment. Data are reported as % inhibition for each concentration tested and IC 50 values are estimated using DataXpress or QPatch software. At least two cells are tested, more if results diverge.

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